(2S,3S)-3-amino-2-hydroxy-4-phenyl-N-[3-(2H-tetrazol-5-yl)phenyl]butanamide | 1023142-92-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: (2S,3S)-3-amino-2-hydroxy-4-phenyl-N-[3-(2H-tetrazol-5-yl)phenyl]butanamide
• CAS: 1023142-92-8
• 化学式: C₁₇H₁₈N₆O₂
• 分子量: 338.369
• InChiKey: OLURYXZPVFAEMF-GJZGRUSLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  25
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  130
• 氢给体数：
  4
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (2S,3S)-3-amino-2-hydroxy-4-phenyl-N-[3-(2H-tetrazol-5-yl)phenyl]butanamide 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 KMI-1731
  参考文献：
  名称：

  Novel BACE1 inhibitors possessing a 5-nitroisophthalic scaffold at the P2 position

  摘要：

  Recently, we reported substrate-based pentapeptidic BACE1 inhibitors possessing a hydroxymethylcarbonyl isostere as a substrate transition-state mimic. These inhibitors showed potent inhibitory activities in enzymatic and cell assays. We also designed and synthesized non-peptidic and small-sized inhibitors possessing a heterocyclic scaffold at the P-2 position. By studying the structure-activity relationship of these inhibitors, we found that the sigma-pi interaction of an inhibitor with the BACE1-Arg235 side chain played a key role in the inhibition mechanism. Hence, we optimized the inhibitors with a focus on their P-2 regions. In this Letter, a series of novel BACE1 inhibitors possessing a 5-nitroisophthalic scaffold at the P-2 position are described along with the results of the related structure-activity relationship study. These small-sized inhibitors are expected improved membrane permeability and bioavailability. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.05.089
• 作为产物：
  描述：

  (2S,3S)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutanoic acid 在 盐酸 、 1-羟基苯并三唑 作用下， 以 1,4-二氧六环 、 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 (2S,3S)-3-amino-2-hydroxy-4-phenyl-N-[3-(2H-tetrazol-5-yl)phenyl]butanamide
  参考文献：
  名称：

  Structure–activity relationship study of BACE1 inhibitors possessing a chelidonic or 2,6-pyridinedicarboxylic scaffold at the P2 position

  摘要：

  We have previously reported potent substrate-based pentapeptidic BACE1 inhibitors possessing a hydroxymethylcarbonyl isostere as a substrate transition-state mimic. While these inhibitors exhibited potent activities in enzymatic and cellular assays (KMI-429 in particular inhibited A beta production in vivo), these inhibitors contained some natural amino acids that seemed to be required to improve enzymatic stability in vivo and permeability across the blood-brain barrier, so as to be practical drug. Recently, we synthesized non-peptidic and small-sized BACE1 inhibitors possessing a heterocyclic scaffold at the P-2 position. Herein we report the SAR study of BACE1 inhibitors possessing this heterocyclic scaffold, a chelidonic or 2,6-pyridinedicarboxylic moiety. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.12.007

文献信息

• NOVEL COMPOUND HAVING SECRETASE INHIBITORY ACTIVITY
  申请人：Kiso, Yoshiaki

  公开号：EP2168947A1

  公开（公告）日：2010-03-31

  A novel compound represented by the formula (1) below which has β-secretase inhibitory activity, its pharmaceutically acceptable salt or a prodrug thereof. wherein Ar is a substituted or unsubstituted 5 to 6 membered mono cyclic aromatic group; R1, R2 and R3 are hydrogen atom, substituted or unsubstituted alkyl group or the like, or R2 and R3 may be taken together with the adjacent nitrogen atom and carbon atom respectively to form a 3 to 6 membered ring; R4 is C1-6 alkyl group, C1-6 alkyl group substituted by phenyl, phenylthio, or a hetero ring, or the like; A is represented by the formula below: wherein X and Y are oxygen atom, NH or sulfur atom, Z is hydrogen atom, hydroxy group which may be substituted, amino group, thiol group, or the like; and B is hydroxy group, substituted or unsubstituted amino group, substituted or unsubstituted aliphatic or aromatic amino group, or the like.

  下面的公式（1）表示的一种新化合物具有β-分泌酶抑制活性，其药用可接受的盐或其前药。其中Ar是取代或未取代的5至6个成员单环芳香基团；R1、R2和R3是氢原子，取代或未取代的烷基或类似物，或R2和R3可以分别与相邻的氮原子和碳原子结合形成3至6个成员环；R4是C1-6烷基，C1-6烷基被苯基，苯硫基或杂环取代，或类似物取代；A由以下公式表示：其中X和Y是氧原子，NH或硫原子，Z是氢原子，可被取代的羟基，氨基，硫醇基等；B是羟基，取代或未取代的氨基，取代或未取代的脂肪或芳香氨基，或类似物。
• Significance of interactions of BACE1–Arg235 with its ligands and design of BACE1 inhibitors with P2 pyridine scaffold
  作者：Yoshio Hamada、Hiroko Ohta、Naoko Miyamoto、Diganta Sarma、Takashi Hamada、Tomoya Nakanishi、Moe Yamasaki、Abdellah Yamani、Shoichi Ishiura、Yoshiaki Kiso

  DOI：10.1016/j.bmcl.2009.03.049

  日期：2009.5

  Recently, we reported potent substrate-based pentapeptidic BACE1 inhibitors possessing a hydroxymethylcarbonyl isostere as a substrate transition-state mimic. Because these inhibitors contained some natural amino acids, we would need to improve their enzymatic stability in vivo and permeability across the blood-brain barrier, so that they become practically useful. Subsequently, non-peptidic and small-sized BACE1 inhibitors possessing a heterocyclic scaffold, 2,6-pyridenedicarboxylic, chelidamic or chelidonic moiety, at the P-2 position were reported. These inhibitors were designed based on the conformer of docked inhibitor in BACE1. In this study, we discuss the role and significance of interactions between Arg235 of BACE1 and its inhibitor in BACE1 inhibitory mechanism. Moreover, we designed more potent small-sized BACE1 inhibitors with a 2,6-pyridinedicarboxylic scaffold at the P2 position, that were optimized for the interactions with Arg235 of BACE1. (c) 2009 Elsevier Ltd. All rights reserved.
• NOVEL COMPOUND HAVING BETA-SECRETASE INHIBITORY ACTIVITY
  申请人：Kiso Yoshiaki

  公开号：US20100137606A1

  公开（公告）日：2010-06-03

  A novel compound represented by the formula (1) below which has β-secretase inhibitory activity, its pharmaceutically acceptable salt or a prodrug thereof. wherein Ar is a substituted or unsubstituted 5 to 6 membered mono cyclic aromatic group; R 1 , R 2 and R 3 are hydrogen atom, substituted or unsubstituted alkyl group or the like, or R 2 and R 3 may be taken together with the adjacent nitrogen atom and carbon atom respectively to form a 3 to 6 membered ring; R 4 is C 1-6 alkyl group, C 1-6 alkyl group substituted by phenyl, phenylthio, or a hetero ring, or the like; A is represented by the formula below: wherein X and Y are oxygen atom, NH or sulfur atom, Z is hydrogen atom, hydroxy group which may be substituted, amino group, thiol group, or the like; and B is hydroxy group, substituted or unsubstituted amino group, substituted or unsubstituted aliphatic or aromatic amino group, or the like.
• US8344002B2
  申请人：——

  公开号：US8344002B2

  公开（公告）日：2013-01-01
• Structure–activity relationship study of BACE1 inhibitors possessing a chelidonic or 2,6-pyridinedicarboxylic scaffold at the P2 position
  作者：Yoshio Hamada、Kenji Suzuki、Tomoya Nakanishi、Diganta Sarma、Hiroko Ohta、Ryoji Yamaguchi、Moe Yamasaki、Koushi Hidaka、Shoichi Ishiura、Yoshiaki Kiso

  DOI：10.1016/j.bmcl.2013.12.007

  日期：2014.1

  We have previously reported potent substrate-based pentapeptidic BACE1 inhibitors possessing a hydroxymethylcarbonyl isostere as a substrate transition-state mimic. While these inhibitors exhibited potent activities in enzymatic and cellular assays (KMI-429 in particular inhibited A beta production in vivo), these inhibitors contained some natural amino acids that seemed to be required to improve enzymatic stability in vivo and permeability across the blood-brain barrier, so as to be practical drug. Recently, we synthesized non-peptidic and small-sized BACE1 inhibitors possessing a heterocyclic scaffold at the P-2 position. Herein we report the SAR study of BACE1 inhibitors possessing this heterocyclic scaffold, a chelidonic or 2,6-pyridinedicarboxylic moiety. (C) 2013 Elsevier Ltd. All rights reserved.